Composition containing ultrafine compounds and its manufacture

Abstract

The present invention provides stable, non-degradable, edible, inhalable, soluble, and drinkable compositions containing highly bioavailable pharmaceutical-grade ultra-fine active pharmaceutical ingredients with 99% purity and 200% increased bioavailability, and methods for their manufacture.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the priority of U.S. Provisional Application No. 62 / 923,726, filed on October 21, 2019, and U.S. Provisional Application No. 62 / 929,455, filed on November 1, 2019, the contents of which are hereby incorporated by reference in their entirety.

[0002] This application relates to a pharmaceutical - grade highly bio - available ultra - fine particle cyclodextrin - encapsulated active pharmaceutical ingredient, a stable and non - degradable edible, inhalable, soluble, and drinkable composition containing the disclosed cyclodextrin - encapsulated active pharmaceutical ingredient, and a method for producing the ultra - fine particle cyclodextrin - encapsulated active pharmaceutical ingredient.

Background Art

[0003] Lipophilic active pharmaceutical ingredients (APIs) are poorly water - soluble, and their extraction and purification are time - consuming processes that require extraction, distillation production, and purification. These processes involve the use of harmful solvents and often produce products plagued by low stability and lack of effectiveness. In addition, the obtained API products lack pharmaceutical - grade purity and have poor bioavailability.

[0004] Cannabinoids are lipophilic APIs that occur naturally in the annual plants Cannabis sativa, Cannabis indica, Cannabis ruderalis, and their hybrids. Tetrahydrocannabinol (THC), the most active naturally occurring cannabinoid, is beneficial in treating a wide range of medical conditions, including glaucoma, AIDS wasting, neuropathic pain, dysphagia associated with multiple sclerosis, fibromyalgia, vomiting, and chemotherapy-induced nausea. Cannabidiol (CBD) has no psychoactive effects and is approved by the FDA for the treatment of epilepsy. Cannabinol (CBN) is an effective sedative and anti-inflammatory agent. There is a growing demand for recreational use of cannabinoids in general, particularly THC, CBD, and CBN. Psychoactive drugs such as psychedelics are also in demand due to their effects on states of consciousness. However, the solubility of these APIs in water is limited. For example, the solubility of currently available cannabidiol (CBD) isolates in water is only 0.0126 mg / ml.

[0005] Cannabinoids are derived from their precursor, cannabigerolic acid (CBGA), or its analogue, cannabigerovalic acid (CBGVA). Enzymatic conversion of CBGA produces a wide variety of cannabinoids, including (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), (-)-trans-Δ9-tetrahydrocannabiphorol ((-)-trans-Δ9-tetrahydrocannabiphorolol) (Δ9-THCP), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabidiol (CBD), cannabinodiol (CBND), and cannabinol (CBN). Enzymatic conversion of CBGVA produces Δ9-tetrahydrocannabivarin (Δ9-THCV), cannabivarin (CBV), cannabidivarin (CBDV), and cannabiclomevarin (CBCV).

[0006] There is a need in the art for the efficient and safe production of stable, non-degradable compositions, including pharmaceutical-grade, inhalable, soluble, and highly bioavailable APIs. [Overview of the project]

[0007] This application presents a solution to the aforementioned problems by providing stable, non-degradable, edible, inhalable, soluble, or ingestible compositions containing pharmaceutical-grade, highly bioavailable ultrafine cyclodextrin-encapsulated active pharmaceutical ingredients, and a rapid, cost-effective, and easily scalable process for producing pharmaceutical-grade, highly bioavailable ultrafine cyclodextrin-encapsulated active pharmaceutical ingredients of high purity. The disclosed process does not require the use of organic solvents and therefore meets the most restrictive health guideline requirements. The resulting ultrafine pharmacoactive ingredients can be used for pulmonary and oral delivery, in food, and for pharmaceutical and medical applications.

[0008] This specification provides stable, non-degradable, edible, inhalable, soluble, or drinkable compositions comprising a pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredient (API) having 99.9% purity and 200% increased bioavailability compared to formulations of non-cyclodextrin-encapsulated active pharmaceutical ingredients, and a pharmaceutically acceptable carrier, excipient, and / or binder.

[0009] Suitable active pharmaceutical ingredients include, but are not limited to, cannabinoids, psychedelics, analgesics, anesthetics, anti-inflammatory agents, antibacterial agents, antiviral agents, anticoagulants, anticonvulsants, antidepressants, and muscle relaxants.

[0010] In some embodiments, the pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of nanoparticles having an average particle size of 100 nm to 40 μm and a size distribution within 1% to 50% of the average particle size.

[0011] In some embodiments, the pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of an ultrafine dry powder having an average particle size of 100 nm to 5 μm.

[0012] In some embodiments, the pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of a soluble or potable solution or suspension.

[0013] In some embodiments, the API is encapsulated in one or more acetylated cyclodextrins. Suitable acetylated cyclodextrins include, but are not limited to, acetylated α-cyclodextrin, acetylated β-cyclodextrin, acetylated γ-cyclodextrin, or any mixture thereof.

[0014] In some embodiments, the API is encapsulated in one or more acetylated cyclodextrins and one or more hydrophilic cyclodextrins. Suitable acetylated cyclodextrins include, but are not limited to, acetylated α-cyclodextrin, acetylated β-cyclodextrin, acetylated γ-cyclodextrin, or any mixture thereof. Suitable hydrophilic cyclodextrins include, but are not limited to, hydrophilic α-cyclodextrin, hydrophilic β-cyclodextrin, hydrophilic γ-cyclodextrin, or any mixture thereof.

[0015] In some embodiments, the API and one or more acetylated cyclodextrins are in a molar ratio of API:acetylated cyclodextrins ranging from 1:0.5 to 1:10. In some embodiments, the molar ratio of API:acetylated cyclodextrins is 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, or 1:10.

[0016] In some embodiments, the API is encapsulated in one or more hydrophilic cyclodextrins. Suitable hydrophilic cyclodextrins include, but are not limited to, hydrophilic α-cyclodextrins, hydrophilic β-cyclodextrins, hydrophilic γ-cyclodextrins, or any mixture thereof.

[0017] In some embodiments, the pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredient is a psychedelic such as psilocin or psilocybin.

[0018] In some embodiments, the pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredient is one or more cannabinoids, such as cannabigerol acid (CBGA), cannabigerovalic acid (CBGVA), tetrahydrocannabinolic acid (THCA), cannabichromenic acid (CBCA), cannabidiolic acid (CBDA), tetrahydrocannabivaric acid (THCVA), cannabiclomevalic acid (CBCVA), cannabidivalic acid (CBDVA), (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), trans-Δ9-tetrahydrocannabifolol (Δ9-THCP), cannabigerol (CBG), cannabichromen (CBC), cannabicyclol (CBL), cannabidiol (CBD), cannabinodiol (CBND), and cannabinol (CBN).

[0019] In some embodiments, the cannabinoid is cannabidiol (CBD). In some embodiments, the cannabinoid is tetrahydrocannabinol (THC). In some embodiments, one or more cannabinoids are cannabidiol (CBD) and tetrahydrocannabinol (THC). In some embodiments, the cannabinoid is cannabinol (CBN). In some embodiments, the cannabinoid is tetrahydrocannabipherol (THCP).

[0020] Suitable pharmaceutically acceptable carriers, excipients, and binders that may be used in the disclosed compositions include, but are not limited to, sodium citrate, dicalcium phosphate, starch, lactose, sucrose, glucose, mannitol, silicic acid, carboxymethylcellulose, alginates, gelatin, lecithin, polyvinylpyrrolidone, sucrose, acacia, humectants, solubilizers, emulsifiers, disintegrants, solution retarding agents, absorption enhancers, wetting agents, absorbents, lubricants, oils, auxiliaries, sweeteners, fragrances, aromatics, buffers, and any mixtures thereof.

[0021] In some embodiments, the disclosed compositions are in the form of inhalers, capsules, tablets, pills, powders, beads, lozenges, dragees, granules, food and beverage compositions, foods, beverages, emulsions, solutions, suspensions, creams, gels, sunscreens, shampoos, toothpastes, transdermal patches, plasters, implants, syrups, elixirs, injections, or infusions.

[0022] In some embodiments, the disclosed compositions are formulated in an immediate-release, sustained-release, or controlled-release form.

[0023] In some embodiments, the disclosed compositions further include coatings. Suitable coatings include, but are not limited to, enteric coatings, extended-release coatings, sustained-release coatings, delayed-release coatings, and immediate-release coatings.

[0024] The disclosed compositions may be formulated for oral, mucosal, pulmonary, topical, parenteral, transdermal, or submucosal administration.

[0025] In some embodiments, the disclosed compositions are in the form of food products. Suitable food products include, but are not limited to, bread, cookies, soups, cereals, salads, sandwiches, sprouts, vegetables, or candies.

[0026] In some embodiments, the disclosed compositions are in the form of a beverage. Suitable beverages include, but are not limited to, tea, juice, syrup, soda, fermented drinks, alcoholic drinks, non-alcoholic drinks, distilled drinks, and brewed drinks.

[0027] The foregoing and other features of the present disclosure will become more apparent from the following detailed description which proceeds with reference to the accompanying drawings.

Brief Description of the Drawings

[0028] The accompanying drawings, which are incorporated herein and constitute a part of this specification, illustrate one or more examples of embodiments and, together with the description of the exemplary embodiments, serve to explain the principles and implementations of the embodiments.

[0029] [Figure 1A] Shows CBD isolate before treatment. The CBD isolate has a crystalline form and a large amount of aggregation between large particles. [Figure 1B] Shows CBD distillate after treatment at a pressure of 3500 psi and a temperature of 40 °C. The particles of the obtained distillate showed a spherical amorphous form and a particle size of 100 nm to 40 μm. [Figure 2A] Shows a 32-fold magnification of purified CBD nanoparticles complexed with α-cyclodextrin with a cannabinoid:cyclodextrin molar ratio of 1:2.5 w / w (250 mg of CBD complexed with 100 mg of α-cyclodextrin) generated by the disclosed method. The CBD nanoparticles have a spherical form and a particle size of 100 nm to 40 μm. [Figure 2B] Shows a 200-fold magnification of purified CBD nanoparticles complexed with α-cyclodextrin with a cannabinoid:cyclodextrin molar ratio of 1:2.5 w / w (250 mg of CBD complexed with 100 mg of α-cyclodextrin) generated by the disclosed method. The CBD nanoparticles have a spherical form and a particle size of 100 nm to 40 μm. [Figure 3]The image shows the crystals of the CBD isolate before processing. The crystals are insoluble in both acid and water. [Figure 4] This shows purified CBD nanoparticles in treated water. The CBD nanoparticles are completely dissolved in the water. [Figure 5] The image shows purified CBD nanoparticles in an acidic solvent similar to the conditions of a stomach after processing. The CBD nanoparticles are completely dissolved in the acidic solution, and the solution is clear. [Figure 6] This is a diagram of the equipment used for the rapid expansion of a supercritical solution. Canister 1 contains a solvent fluid such as CO2 (99.0%), inlet valve 2 opens and controls the flow to the inlet of HPLC pump 3, outlet valve 4 opens and controls the flow of high-pressure solvent to extraction vessel 8, pressure gauge 5 indicates the pressure of the solvent in the inlet line and in extraction vessel 8, thermometer 6 indicates the internal temperature of extraction vessel 8, heating band 7 adjusts the internal heat of extraction vessel 8, extraction vessel 8 contains the solute to be mixed and dissolved in the supercritical fluid, spray valve 9 distributes the supercritical solution in the extraction vessel through spray nozzle 11 into the precipitate / collection chamber 10 where the process is carried out and the final product is collected, and pressure reaction valve or vent 12 reduces the pressure in the precipitate / collection chamber 10. [Figure 7] Simplified apparatus for several embodiments of the process provided herein is shown. API and one or more acetylated cyclodextrins are introduced into a heating and pressurizing vessel 1 via a supply valve. Supercritical, subcritical, high-pressure gaseous or liquid carbon dioxide is then released from a CO2 tank via a supply valve 5, cooled in a cooling chamber 3, and pumped by a pump 4 into the heating and pressurizing vessel 1 via an inlet valve 6 to dissolve the API and acetylated cyclodextrins into a cyclodextrin-encapsulated API solution. This solution then passes through a transfer valve 8, is depressurized via a nozzle 9 using a short burst, and collected in a powder collection container 2, where it is sorted by particle size via a final product outlet 10. [Figure 8]A simplified apparatus for additional embodiments of the process provided herein is shown. One or more hydrophilic cyclodextrins are supplied into a heating and pressurizing vessel 12 via a supply valve 22 and dissolved in a hydrophilic liquid at a controlled pressure and temperature via a pressure control valve 21 to form an aqueous hydrophilic cyclodextrin solution. The API is introduced into the heating and pressurizing vessel 11 via a supply valve 17. Supercritical, subcritical, high-pressure gaseous or liquid carbon dioxide is then released from a CO2 tank via a supply valve 15, cooled in a cooling chamber 13, and pumped into the heating and pressurizing vessel 11 via an inlet valve 16 by a pump 14 to dissolve the API. This API solution is then depressurized via a nozzle 19 using a short burst and passed through a transfer valve 18 into the heating and pressurizing vessel 12, and droplets of the API solution are dispersed in the aqueous cyclodextrin solution. The thus formed water-soluble hydrophilic API concentrate is collected via an outlet 20 for the final product. [Figure 9] The solubility profile of cyclodextrin-encapsulated API samples is shown compared to unprocessed API containing an equivalent amount of API. [Modes for carrying out the invention]

[0030] The following definitions of terms are provided to better describe this disclosure and to guide those skilled in the art in practicing this disclosure. As used herein, “comprising” means “including” and does not mean to exclude elements of compositions and methods that are not enumerated. As used to define compositions and methods, “essentially consisting of” means to exclude any other elements of any essential importance to the combination. For example, a composition essentially consisting of elements as defined herein does not exclude other elements that do not substantially affect the basic and novel features of the claimed invention. “Consists of” means to exclude any other enumerated components and substantial method steps in excess of trace amounts. The singular “a,” “an,” or “the” includes multiple references unless the context explicitly indicates otherwise. The term “or” refers to a single element or a combination of two or more elements of the alternative elements stated, unless the context explicitly indicates otherwise. All numerical notations, including ranges, such as pH, temperature, time, concentration, quantity, and molecular weight, are approximations that vary by (+) or (-) 10%, 1%, or 0.1%, as appropriate. It should also be understood that, although not necessarily expressly stated, the reagents described herein are merely illustrative, and equivalents of such reagents are known in the art. Unless otherwise stated, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. Materials, methods, and examples are illustrative and not intended to limit the scope.

[0031] To facilitate an overview of the various embodiments of this disclosure, the following explanations of specific terms are provided.

[0032] Approximately: A term used to indicate a change in value by + / - 10% of the value, or optionally + / - 5% of the value, or in some embodiments, + / - 1% of the value.

[0033] Administration: Providing or administering a composition, such as a supplement composition, to a subject via an effective route. Application is topical. Exemplary routes of application include, but are not limited to, oral and topical routes.

[0034] Agitation or stirring: A mechanical action that includes, but is not limited to, any action that causes rotation, vibration, vortexing, swirling, shaking, ultrasonic, stirring, or mixing. Examples of mechanical actions include actions performed by hand or by a rotating device.

[0035] Active pharmaceutical ingredient: A biologically active component in a finished product that has a direct effect on the diagnosis, treatment, mitigation, management, or prevention of a disease, or on the restoration, correction, or modification of one or more physiological functions in a subject such as a human or animal.

[0036] Alcohol: An organic compound containing a hydroxyl functional group (-OH) bonded to a carbon atom.

[0037] Analogue: A compound that has a similar structure to another compound, but differs from it in, for example, one or more atoms, functional groups, or substructures. API analogues include compounds that are structurally related to naturally occurring APIs but whose chemical and biological properties may differ from those of naturally occurring APIs, as well as compounds derived from naturally occurring APIs through chemical, biological, or semisynthetic transformations of naturally occurring APIs.

[0038] Cannabinoids: A class of diverse chemical compounds that activate cannabinoid receptors. Cannabinoids produced by plants are called phytocannabinoids. Typical cannabinoids isolated from cannabis plants include, but are not limited to, tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarin (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabiclomevalin (CBCV), cannabigerovarin (CBGV), and cannabigerol monomethyl ether (CBGM).

[0039] Cell: A living biological cell that may be identical or different from its parent cell, its offspring or potential offspring.

[0040] To bring into contact: To place in a direct physical meeting.

[0041] Co-solvent: A solvent added to a fluid in an amount less than 50% of its total volume.

[0042] Cyclodextrins are a family of cyclic oligosaccharides produced from starch by enzymatic conversion, possessing a structure containing a macrocyclic ring of α-D-glucopyranoside units linked by α-1,4 glycosidic bonds. Typical cyclodextrins contain 6 to 8 glucose subunits within the ring, forming a conical shape. α-cyclodextrins contain 6 glucose subunits, β-cyclodextrins contain 7 glucose subunits, and γ-cyclodextrins contain 8 glucose subunits. Because cyclodextrins have a hydrophobic inner core and a hydrophilic outer layer, they form complexes with hydrophobic compounds.

[0043] Effective dose: The amount of an active agent (alone or in combination with one or more other active agents) sufficient to induce a desired response, e.g., sufficient to prevent, treat, reduce and / or improve a condition.

[0044] Emulsifiers: Surfactants that reduce the interfacial tension between oil and water, minimizing surface energy due to droplet formation. Examples of emulsifiers include gums, fatty acid conjugates, and cationic, anionic, and amphiphilic surfactants, which can stabilize the emulsion by suspending the oil phase, coating the oil droplets, and preventing separation of the internal oil phase. The film coating produced by the emulsifier is a barrier between immiscible phases, which also prevents the aggregation, coagulation, and adhesion of droplets. Examples of emulsifiers include lecithin, glyceryl monostearate, methylcellulose, sodium lauryl sulfate, sodium oleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristrearate, tragacanth, triethanolamine oleate, polyethylene sorbitan monolaurate, poloxamer, detergents, Tween 80 (polyoxyethylene sorbitan monooleate), Tween 20 (polyoxyethylene sorbitan monolaurate), cetearyl glucoside, polyglucoside, sorbitan monooleate (Span 80), sorbitan monolaurate (Span 20), polyoxyethylene monostearate (Myrj 45) Examples include, but are not limited to, polyoxyethylene vegetable oil (Emulphor), cetylpyridinium chloride, polysaccharide gums, xanthan gum, tragacanth, arabica gum, acacia, or proteins and conjugated proteins that can form and protect stable oils in glycerin emulsions.

[0045] Hydrophilicity: A polymer, substance, or compound that can absorb more than 10% water at 100% relative humidity (RH).

[0046] Hydrophobic: A polymer, substance, or compound that can absorb less than 1% water at 100% relative humidity (RH).

[0047] Lipophilicity: A substance or compound that has an affinity for non-polar environments compared to polar or aqueous environments.

[0048] Nanoparticles: Particles of an object that can be measured on a nanometer scale. Nanoparticles can be in solid or semi-solid form.

[0049] Oil: Any fatty substance that exists in the form of a viscous liquid at room temperature (25°C) and atmospheric pressure (760 mmHg). Oils are hydrophobic and lipophilic, have high carbon and hydrogen content, and are usually flammable and surface-active. Oils can be of animal, vegetable, or petrochemical origin and can be volatile or non-volatile. Oils can be used for food, fuel, medical purposes, and in the manufacture of paints and plastics.

[0050] Organic solvent: A hydrocarbon solvent that selectively contains one or more polar groups and can dissolve substances that have low solubility in water.

[0051] Permeability enhancers: Natural or synthetic molecules that facilitate the transport of co-administered active drugs across biological membranes.

[0052] pH adjusters or pH modifiers: Molecules or buffers used in a formulation to achieve a desired pH control. Exemplary pH modifiers include acids (e.g., acetic acid, adipic acid, carbonic acid, citric acid, fumaric acid, phosphoric acid, sorbic acid, succinic acid, tartaric acid), basic pH modifiers (e.g., magnesium oxide, tribasic potassium phosphate), and pharmaceutically acceptable salts thereof.

[0053] Psychedelic drugs: Hallucinogens that induce abnormal states of consciousness and psychedelic experiences through serotonin 2A receptor agonism.

[0054] Purification or cleansing: Any technique or method to increase the degree of purity of a substance of interest, such as an enzyme, protein, or compound from a sample containing the substance of interest. Non-limiting examples of purification methods include, but are not limited to, silica gel column chromatography, size exclusion chromatography, hydrophobic interaction chromatography, ion exchange chromatography, free-flow electrophoresis, high-performance liquid chromatography (HPLC), and differential precipitation.

[0055] Purity: The quality of the product obtained by the disclosed method, free from contamination, unspoiled, and safe to pharmaceutical standards.

[0056] Recovery: A process involving the isolation and collection of products from a reaction mixture. Recovery methods may include, but are not limited to, chromatography, e.g., silica gel chromatography and HPLC, activated carbon treatment, filtration, distillation, precipitation, drying, chemical extraction, and any combination thereof.

[0057] Supercritical fluid: Any substance that exists at temperatures and pressures above its critical point and does not have distinct liquid and gas phases. The solubility of a material in a fluid increases as the density of the fluid increases. The density of a fluid increases with pressure, and at a constant density, the solubility of a material in the fluid increases as the temperature increases. Exemplary supercritical fluids include, but are not limited to, carbon dioxide, water, methane, propane, ethane, ethylene, propylene, methanol, ethanol, acetone, and nitrogen oxides.

[0058] Viscosity: A measure of a fluid's resistance to gradual deformation due to shear or tensile stress.

[0059] Water immiscibility: Any non-aqueous or hydrophobic fluid, liquid, or solvent that separates into two distinct phases when mixed with water.

[0060] Water-insoluble: A compound or composition having a water solubility of less than 5%, less than 3%, or less than 1%, as measured in water at 20°C.

[0061] Method for producing highly bioavailable, edible, inhalable, soluble, or ingestible pharmaceutical-grade pure active pharmaceutical ingredients. The development of efficient processes for producing pure lipophilic API compounds with high bioavailability has been hindered to date by the low solubility of APIs in aqueous and acidic conditions. As a result, conventional preparation and purification of lipophilic APIs are time-consuming processes, often requiring the use of toxic organic solvents. Furthermore, APIs produced by currently available methods suffer from a lack of purity and low bioavailability.

[0062] Disclosed herein is a rapid and efficient method for overcoming these challenges by using supercritical, subcritical, high-pressure gaseous, or liquid carbon dioxide, as well as acetylated and / or hydrophilic cyclodextrins, to produce high-purity, ultrafine API-cyclodextrin-containing complexes suitable for pulmonary and oral delivery. The method provided herein significantly reduces API particle size, does not involve the use of toxic organic solvents, and produces pure active pharmaceutical compounds that meet the most restrictive health requirements. Cyclodextrin encapsulation protects the API from degradation after production, so the pure active pharmaceutical compounds produced according to the disclosed method are extremely stable over long periods, such as 16 months or more at room temperature, and do not degrade over time. In addition, since carbon dioxide is a gas at atmospheric pressure, CO2 removal is much faster and safer than organic solvent removal, and no residual solvent remains in the final product.

[0063] Accordingly, in some embodiments, a method is provided that includes (i) dissolving an API and one or more acetylated cyclodextrins in supercritical, subcritical, high-pressure gas or liquid carbon dioxide in a reaction chamber; (ii) pumping carbon dioxide at a set pressure and a set temperature for a predetermined period of time to obtain an acetylated cyclodextrin-encapsulated API solution; (iii) reducing the pressure of the acetylated cyclodextrin-encapsulated API solution; (iv) spraying the acetylated cyclodextrin-encapsulated API solution through a nozzle into a heated precipitate to obtain inhalable ultrafine nanoparticles of the acetylated cyclodextrin-encapsulated active pharmaceutical ingredient; and (v) collecting and sorting the inhalable ultrafine nanoparticles of the acetylated cyclodextrin-encapsulated active pharmaceutical ingredient by particle size.

[0064] The disclosed method generates inhalable, pharmaceutical-grade, highly bioavailable ultrafine nanoparticles of cyclodextrin-encapsulated active pharmaceutical ingredients. The inhalable ultrafine nanoparticles have an average particle size of 100 nm to 40 μm and a size distribution within approximately 1% to 50% of the average particle size. The ultrafine nanoparticles can also be added to foods such as solid foods, beverages, condiments, and dietary supplements, and can be used in medical and pharmaceutical applications in immediate-release, sustained-release, and controlled-release formulations for long-term and sustained effects.

[0065] In some embodiments, the process involves (i) grinding hydrophilic cyclodextrin into particles having an average particle size of 100 nm to 5 μm, (ii) dissolving the API and one or more acetylated cyclodextrins in supercritical, subcritical, high-pressure gas, or liquid carbon dioxide in a reaction chamber, (iii) pumping carbon dioxide at a set pressure and temperature for a predetermined period of time to obtain an acetylated cyclodextrin-encapsulated API solution, and (iv) reducing the pressure of the acetylated cyclodextrin-encapsulated API solution. A method is provided which includes (v) adding hydrophilic cyclodextrin particles to an acetylated cyclodextrin-encapsulated API solution to prepare a hydrophilic cyclodextrin suspension-acetylated cyclodextrin-encapsulated API solution mixture; (vi) spraying the mixture into a heated precipitate through a nozzle to obtain an inhalable ultrafine dry powder of the cyclodextrin-encapsulated active pharmaceutical ingredient; and (vii) collecting and sorting the inhalable ultrafine dry powder of the cyclodextrin-encapsulated active pharmaceutical ingredient according to particle size.

[0066] The disclosed method produces a pharmaceutical-grade, highly bioavailable, ultrafine, inhalable dry powder of a cyclodextrin-encapsulated active pharmaceutical ingredient. The particle size of the dry powder can be varied by determining the particle size of the hydrophilic cyclodextrin rather than by dissolving and forming a suspension in carbon dioxide. The hydrophobicity of the inhalable dry powder is controlled by adjusting the ratio between acetylated cyclodextrin and hydrophilic cyclodextrin. The dry powder thus produced is readily soluble in water, hydrophilic liquids, brewed or fermented alcoholic and non-alcoholic beverages, juices, and can be added to foods such as solid foods, beverages, condiments, and dietary supplements, and can be used in medical and pharmaceutical applications in immediate-release, sustained-release, and controlled-release formulations for long-term and sustained effects.

[0067] In additional embodiments, a method is provided comprising: (i) dissolving a hydrophilic cyclodextrin in a hydrophilic liquid at controlled pressure and temperature to form a hydrophilic cyclodextrin aqueous solution; (ii) dissolving the API in supercritical, subcritical, high-pressure gas or liquid carbon dioxide in a reaction chamber; (iii) pumping carbon dioxide at a set pressure and temperature for a predetermined period of time to obtain an API solution; (iv) reducing the pressure of the API solution; and (v) spraying the API solution through a nozzle into a hydrophilic cyclodextrin aqueous solution to obtain a drinkable solution or suspension of the hydrophilic cyclodextrin-encapsulated active pharmaceutical ingredient. The hydrophilic liquid may optionally include, but is not limited to, water, juice, syrup, milk, or alcoholic beverages containing excipients. In some embodiments, the controlled pressure is 50 to 100 bars and the controlled temperature is 30 to 70°C. By spraying an API solution into an aqueous cyclodextrin solution, API droplets are formed that disperse in the aqueous cyclodextrin solution, producing a water-soluble cyclodextrin-encapsulated API concentrate. The aqueous cyclodextrin solution may contain stabilizers, thickeners, and surfactants to improve the stability of the API compound in the solution.

[0068] The disclosed method is for producing a pharmaceutical-grade, highly bioavailable, soluble or potable solution or suspension containing an ultrafine cyclodextrin-encapsulated active pharmaceutical ingredient. The cyclodextrin-encapsulated API solutions and suspensions are ready for consumption without any further preparation and can be diluted in water, hydrophilic liquids, brewed or fermented alcoholic and non-alcoholic beverages, juices, or any other potable liquid.

[0069] Suitable active pharmaceutical ingredients that can be processed according to the disclosed method include, but are not limited to, any form of cannabinoid, psychedelic, analgesic, anesthetic, anti-inflammatory, antibacterial, antiviral, anticoagulant, anticonvulsant, antidepressant, and muscle relaxant.

[0070] APIs may be in the form of crude plant extracts, distillates, purified distillates, double purified distillates, triple purified distillates, or isolates. Plant extracts may contain plant materials such as lipids and waxes, chlorophyll, and terpenes such as myrcene, geraniol, limonene, terpineol, pinene, menthol, thymol, carvacrol, camphor, and sesquiterpenes. Distillates can be prepared by mixing the extract with alcohol, filtering the mixture to remove plant materials, and then heating to remove the alcohol. For further purification, the distillate can be heated and subjected to short-path distillation, and this process can be repeated several times to obtain double purified distillates, triple purified distillates, or isolates of higher purity. In alternative embodiments, APIs may be in crystalline form.

[0071] Suitable cannabinoids and cannabinoid precursors include, but are not limited to, cannabigerol acid (CBGA), cannabigerovalic acid (CBGVA), tetrahydrocannabinolic acid (THCA), cannabichromenic acid (CBCA), cannabidiolic acid (CBDA), tetrahydrocannabivaric acid (THCVA), cannabiclomevalic acid (CBCVA), cannabidivalic acid (CBDVA), (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), (-)-trans-Δ9-tetrahydrocannabiferol (Δ9-THCP), cannabigerol (CBG), cannabichromen (CBC), cannabicyclol (CBL), cannabidiol (CBD), cannabinodiol (CBND), cannabinol (CBN), their analogues, or any mixture thereof.

[0072] Suitable psychedelics include, but are not limited to, psilocine and psilocybin.

[0073] In some embodiments, the methods disclosed herein provide acetylation of cyclodextrins to increase Lewis acid-Lewis base interactions between cyclodextrins and carbon dioxide, thereby significantly increasing their solubility. In other embodiments, the methods disclosed herein provide the use of actylated cyclodextrins to increase the solubility of APIs in carbon dioxide, and hydrophilic cyclodextrins to form inhalable powders of ultrafine cyclodextrin-encapsulated APIs. In other embodiments, the methods disclosed herein provide the use of hydrophilic cyclodextrins to disperse API droplets and produce water-soluble API concentrates.

[0074] Suitable cyclodextrins include, but are not limited to, α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin. Suitable acetylated forms of cyclodextrins include, but are not limited to, α-cyclodextrin exadeacetate (AACD), β-cyclodextrin heneicosaacetate (ABCD), and γ-cyclodextrin octadeacetate (AGCD), respectively. Suitable hydrophilic cyclodextrins include, but are not limited to, hydrophilic α-cyclodextrin, hydrophilic β-cyclodextrin, hydrophilic γ-cyclodextrin, and any mixture thereof.

[0075] For processing, API extracts, distillates, purified distillates, double purified distillates, triple purified distillates, or high-quality isolates can be combined with acetylated and / or hydrophilic cyclodextrins in an API:cyclodextrin molar ratio ranging from 1:0.5 to 1:10. In some examples, the API:cyclodextrin molar ratios are 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, or 1:10.

[0076] APIs and cyclodextrins can be mixed over a period defined by the type and form of API used, the type of cyclodextrin used, the temperature and pressure conditions, and the force used for mixing. In some embodiments, the preset pressure is in the range of 2,500 psi to 6,500 psi, and the preset temperature is in the range of 37°C to 55°C. After pressurization, the API solution is depressurized supersonic and released through a nozzle in short bursts to induce particle formation. The nozzle diameter is in the range of 1 μm to 10 μm. In some embodiments, the nozzle diameter is 1 μm, 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, or 7 μm. Depressurization is best achieved by releasing the supercritical solution through the nozzle in short bursts, such as bursts of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 second.

[0077] Supercritical, subcritical, high-pressure gaseous, or liquid carbon dioxide may contain excipients or dispersants. In some embodiments, the disclosed method may further include (vi) converting carbon dioxide into a gas; (vii) filtering and pressurizing the carbon dioxide gas to achieve a supercritical, subcritical, high-pressure gaseous, or liquid state; and (viii) recirculating the carbon dioxide in a reaction chamber for subsequent batch processing.

[0078] The cannabinoid fine nanoparticles produced by the method provided herein have an average particle size of about 100 nm to about 40 μm and a size distribution of about 1% to about 50% of the average particle size.

[0079] The method provided herein offers numerous advantages. In particular, the disclosed method significantly reduces API particle size, does not require the use of toxic organic solvents, and rapidly and efficiently produces high-purity, ultrafine API-cyclodextrin-encapsulated complexes in the form of nanoparticles, dry powders, solutions, and suspensions suitable for pulmonary and / or oral delivery. The cyclodextrin-encapsulated APIs produced by the disclosed method are 99.9% pure, have 200% increased bioavailability compared to formulations of non-cyclodextrin-encapsulated active pharmaceutical ingredients, and exhibit excellent stability at room temperature over long periods such as 16 months, 24 months, 3 years, 4 years, and 5 years.

[0080] Apparatus for producing pharmaceutical-grade pure ultrafine cyclodextrin-encapsulated APIs Figures 6, 7, and 8 illustrate exemplary apparatus for carrying out the disclosed method. However, the method provided herein can be carried out using any apparatus, system, or device known in the art.

[0081] In the diagram shown in Figure 6, canister 1 contains a 99% pure fluid such as CO2. Inlet valve 2 opens and controls the flow of solvent fluid to the inlet, which accesses the HPLC pump 3. Outlet valve 4 opens and controls the flow of high-pressure solvent to the extraction vessel 8. A pressure gauge 5, integrated as part of the HPLC pump, indicates the pressure of the solvent in the inlet line and in the extraction vessel 8. A thermometer 6 indicates the internal temperature of the extraction vessel 8. A heating band 7 adjusts the internal heat level of the extraction vessel 8. The extraction vessel 8 contains API with or without acetylated cyclodextrin to be dissolved in CO2. Once the API solution is formed, a spray valve 9 depressurizes the API solution in the extraction vessel by releasing the solution through a spray nozzle 11 into a precipitation chamber 10 where the final product is collected. A pressure reaction valve or vent 12 reduces the pressure in the precipitation chamber 10, resulting in the spontaneous formation of ultrafine API nanoparticles or dry powder, which can then be collected and sorted according to their size.

[0082] In the diagram shown in Figure 7, the API and one or more acetylated cyclodextrins are inserted into the heating and pressurizing vessel 1 via a supply valve. Supercritical, subcritical, high-pressure gaseous or liquid carbon dioxide is then released from the CO2 tank via the supply valve 5, cooled in the cooling chamber 3, and pumped by the pump 4 into the heating and pressurizing vessel 1 via the inlet valve 6, dissolving the API and acetylated cyclodextrins into the cyclodextrin-encapsulated API solution. This solution then passes through the transfer valve 8, is depressurized via the nozzle 9 using a short burst, collected in the powder collection container 2, and sorted by particle size via the final product outlet 10.

[0083] In the diagram shown in Figure 8, one or more hydrophilic cyclodextrins are supplied into the heating and pressurizing vessel 12 via a supply valve 22 and dissolved in a hydrophilic liquid at a controlled pressure and temperature via a pressure control valve 21 to form an aqueous hydrophilic cyclodextrin solution. The API is then introduced into the heating and pressurizing vessel 11 via a supply valve 17. Supercritical, subcritical, high-pressure gas or liquid carbon dioxide is then released from the CO2 tank via a supply valve 15, cooled in a cooling chamber 13, and pumped into the heating and pressurizing vessel 11 via an inlet valve 16 by a pump 14 to dissolve the API. This API solution then passes through a transfer valve 18 and is depressurized via a nozzle 19 in a short burst into the heating and pressurizing vessel 12, and droplets of the API solution are dispersed in the aqueous cyclodextrin solution. The resulting water-soluble hydrophilic API concentrate is collected via the final product outlet 20.

[0084] Pharmaceutical-grade ultrafine cyclodextrin encapsulated API In addition, this specification provides stable, edible, inhalable, soluble, or ingestible pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredients produced by the disclosed method. These stable, edible, inhalable, soluble, or ingestible pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredients have a purity of 99.9% and a 200% increase in bioavailability compared to formulations of non-cyclodextrin-encapsulated active pharmaceutical ingredients. The active pharmaceutical ingredients may be cannabinoids, psychedelics, analgesics, anesthetics, anti-inflammatory agents, antibacterial agents, antiviral agents, anticoagulants, anticonvulsants, antidepressants, or muscle relaxants.

[0085] In some embodiments, the pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of inhalable nanoparticles having an average particle size of 100 nm to 40 μm and a size distribution of 1% to 50% of the average particle size.

[0086] In some embodiments, the pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of an inhalable ultrafine dry powder having an average particle size of 100 nm to 5 μm.

[0087] In some embodiments, the pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of an orally drinkable or soluble solution or suspension.

[0088] The disclosed edible, inhalable, soluble, or drinkable pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredients can be easily manufactured, mixed with other edible ingredients or preparations, and consumed or distributed without any risk of resuspension or separation due to their stability. In particular, the disclosed edible, inhalable, soluble, or drinkable pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredients are fully soluble in water, have an average bioavailability increased by 200% (+ / - 10%) compared to non-cyclodextrin-encapsulated active pharmaceutical ingredients, and can be stored indefinitely after production.

[0089] Composition containing pharmaceutical-grade ultrafine cyclodextrin-encapsulated API The disclosed edible, inhalable, soluble, or drinkable pharmaceutical-grade cyclodextrin-encapsulated active pharmaceutical ingredients may be formulated as compositions for oral, pulmonary, enteral, parenteral, intravenous, topical, mucosal, and submucosal administration, such as prescribed, unprescribed, and retail offerings of medical and pharmaceutical products, for the treatment, prevention, and relief of diseases, disorders, illnesses, and complaints, including but not limited to Alzheimer's disease, epilepsy, mild and chronic pain, chemotherapy-induced peripheral neuropathy, insomnia, opioid and drug addiction, addiction prevention, inflammatory lung disease, anxiety disorders, PTSD, panic attacks, phobias, allergies, coronavirus, asthma and COPD, and Meniere's disease.

[0090] The disclosed compositions can be formulated in immediate-release, sustained-release, or controlled-release forms and can be coated with compounds that enhance or reduce API release. Accordingly, the disclosed compositions may include enteric coatings, extended-release coatings, sustained-release coatings, delayed-release coatings, and immediate-release coatings. Methods used to coat the compositions, as well as materials used to manufacture such coatings, are well known in the field of pharmaceutical formulation. Examples of coating materials include, but are not limited to, glyceryl monostearate, glyceryl distearate, polymeric substances, and waxes.

[0091] Suitable solid drug formulations for oral administration include, but are not limited to, capsules, tablets, pills, powders, beads, lozenges, dragees, granules, aerogels, crumbles, and snaps. Such solid drug delivery forms include at least one excipient or carrier that is pharmaceutically acceptable, e.g., sodium citrate or dicalcium phosphate; fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; humectants, e.g., glycerol; disintegrants, e.g., agar, calcium carbonate, potato or tapioca starch, alginic acid, silicates, and sodium carbonate; solution retarders, e.g., paraffin; absorption enhancers, e.g., quaternary ammonium compounds; wetting agents, e.g., acetyl alcohol and glycerol monostearate; absorbents, e.g., kaolin and bentonite clay; lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and buffers.

[0092] The solid oral dosage form can also be formulated as an edible composition and may include any edible preparation containing the disclosed cannabinoid nanoparticles mixed with food. The food can be dried, cooked, boiled, freeze-dried or baked and may be in the form of bread, cookies, tea, juice, soup, cereal, salad, sandwich, sprouts, vegetables, candy, pills, tablets, etc.

[0093] Examples of liquid medication forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs, and may contain inert diluents commonly used in the art. For example, a liquid formulation may contain water, polyethylene glycol ether, or any other pharmaceutically acceptable solvent; solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, and dimethylformamide; oils, such as cottonseed, peanut, corn, germ, olive, castor, and sesame oil; fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan; auxiliaries, such as wetting agents; emulsifiers and suspending agents, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, sorbitan esters, microcrystalline cellulose, aluminum methhydroxyl, bentonite, agar, tragacanth, and mixtures thereof; sweeteners, flavorings, fragrances, and any mixtures thereof.

[0094] The liquid oral dosage form can also be formulated as an edible composition and may include any ingestible preparation containing the disclosed cannabinoid nanoparticles mixed with a beverage product. Examples of beverage products include, but are not limited to, tea, juice, syrup, soup, soda, brewed drinks, fermented drinks, and distilled drinks.

[0095] Parenteral administration methods include subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, or infusion techniques. Parenteral administration suspensions can be encapsulated using various polymers, sugars, and chelating agents to obtain stable preparations or granules. Examples of polymers for encapsulation include cross-linked polymers, non-cross-linked polymers, or polymers dispersed within the crystalline structure of sugar starch or protein molecules. Granules can be further processed to obtain sublingual membranes, suppositories, dispersible powders, tablets, gel capsules, and the like.

[0096] Compositions for parenteral injection may include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injection solutions or dispersions before use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include, but are not limited to, water, ethanol, polyols such as glycerol, propylene glycol, and polyethylene glycol, carboxymethylcellulose and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Adequate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Compositions disclosed for parenteral administration may also contain adjuvants, for example, but not limited to, preservatives, wetting agents, emulsifiers, and dispersants, isotonic agents such as sugars and sodium chloride, and absorption-delaying agents such as aluminum monostearate and gelatin.

[0097] Injectable depot formulations can be prepared by forming a matrix of the API in biodegradable polymers, for example, but not limited to, polylactide-polyglycolide, poly(orthoester), and poly(anhydride). Injectable formulations of the depot can also be prepared by encapsulating the disclosed API in liposomes compatible with in vivo tissues. Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium immediately before use.

[0098] The disclosed compositions can be prepared in the form of inhalation preparations for pulmonary delivery. Suitable preparations include, but are not limited to, aerosols, inhalers, respiratory activators, dry powder inhalers, capsules and blister inhalers, multi-dose inhalers, measuring inhalers, vaporizers, sprays, and nasal sprays, and may include various carriers or excipients known in the formulation field.

[0099] Topical compositions may be in the form of powders, liquid solutions, emulsions, liquid suspensions, creams, ointments, gels, gum gels, mouthwashes, sunscreens, toothpastes, shampoos, conditioners, or liquid soaps, and can be applied to the face, eyes, lips, teeth, hair, forehead, nails, hands, feet, shoulders, arms, back, or legs of the subject. Suitable subjects include mammals, such as animals or humans.

[0100] The disclosed compositions may be in the form of patches, wound dressings, plasters, gypsum, stents, implants, aerogels, crumbles, snaps, or hydrogels for transdermal application, and may be formulated for immediate release, extended release, or sustained release. Various additives known to those skilled in the art may be included in the transdermal formulation. Examples of additives include, but are not limited to, solubilizers, skin permeability enhancers, preservatives, such as antioxidants, humectants, gelling agents, buffers, surfactants, emulsifiers, emollients, thickeners, stabilizers, humectants, dispersants, and pharmaceutical carriers. Examples of humectants include, but are not limited to, jojoba oil and evening primrose oil. Suitable skin permeability enhancers include, but are not limited to, lower alkanols, e.g., methanol-ethanol and 2-propanol; alkyl methyl sulfoxides, e.g., dimethyl sulfoxide (DMSO), decyl methyl sulfoxide (C10 MSO), and tetradecyl methyl sulfoxide; pyrrolidone, urea; N,N-diethyl-m-toluamide; C2-C6 alkanediols, dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and tetrahydrofurfuryl alcohol. Examples of solubilizers include, but are not limited to, hydrophilic ethers, e.g., diethylene glycol monoethyl ether and diethylene glycol monoethyl ether oleate; polyoxy-35 castor oil, polyoxy-40 hydrogenated castor oil, polyethylene glycol (PEG), and polyethylene glycol derivatives, e.g., PEG-8 caprylic / capric acid glyceride; alkyl methyl sulfoxides, e.g., DMSO; pyrrolidone, DMA, and mixtures thereof.

[0101] Prevention and / or treatment of infection can be achieved by including antibiotics, as well as various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenolsorbic acid, etc., in the disclosed compositions.

[0102] The disclosed compositions may also be administered by various other routes, including mucosal, subcutaneous, and intramuscular administration, and may include various carriers or excipients known in the formulation field, such as non-toxic solids, semi-solids, or liquid fillers, diluents, encapsulating materials, and pharmaceutically acceptable formulation aids.

[0103] The disclosed compositions may include various carriers or excipients known in the formulation field, such as non-toxic solids, semi-solids or liquid fillers, diluents, encapsulating materials, and pharmaceutically acceptable excipients, diluents, auxiliaries, stabilizers, emulsifiers, preservatives, colorants, buffers, fragrance agents, bacteriostatic agents, fungicides, emollients, plasticizers, permeability enhancers, antioxidants, pigments, lubricants, preservatives, wetting agents, salts, and any mixtures thereof. [Examples]

[0104] Example 1: Cannabinoid extract, distillate, and isolate Cannabinoid precursors, cannabigerolic acid (CBGA) and cannabigerovalic acid (CBGVA), were obtained by extraction from the Cannabis plant or purchased commercially. Cannabinoids, specifically tetrahydrocannabinolic acid (THCA), cannabinolic acid (CBDA), cannabichromenic acid (CBCA), (-)-trans-Δ9-tetrahydrocannabinolic acid (Δ9-THCA), tetrahydrocannabivalic acid (THCVA), cannabiclomevalic acid (CBCVA), and cannabidivalic acid (CBDVA), were extracted from the Cannabis sativa plant by organic solvent extraction, steam extraction, or supercritical fluid extraction. The neutral forms of cannabinoids, tetrahydrocannabinol (THC), cannabidiol (CBD), (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabidiol (CBD), cannabinodiol (CBND), and cannabinol (CBN), were obtained by decarboxylation of their corresponding acidic forms by heating, drying, or combustion. For decarboxylation by heating, the cannabinoid extracts were heated at 95°C for approximately 20 minutes until melted, and then cooled in a freezer for approximately 15 minutes.

[0105] Cannabinoid extracts were subjected to molecular distillation, and the distillates were purified by removing terpenes, organic materials, and chlorophyll using thin-layer chromatography (THLC), high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry, and / or gas chromatography-flame ionization detector (GC-FID) analysis.

[0106] The cannabinoid liquid oil distillate obtained as described above was used as is. Alternatively, the purified cannabinoid liquid oil distillate was purified again to obtain cannabinoids that were distilled twice. By purifying the cannabinoids that were distilled twice a third time, a highly pure cannabinoid isolate that was distilled three times was obtained.

[0107] Example 2: Prior Test As disclosed herein, fine nanoparticles were prepared. The system was optimized to minimize the effects of humidity by washing with CO2 before cannabinoid addition, and the pressure release process was optimized to 0.5 seconds using a 25-second repressurization cycle to prevent nozzle freezing and ensure uniformity and reproducibility.

[0108] Cannabinoids in the form of extracts, distillates, or isolates were added to a 10 ml high-pressure reactor chamber, and liquid CO2 was pumped into the reactor chamber at a pressure of 1000 psi. The reactor was heated to 40°C, and the pressure was increased in the range of approximately 1500 psi to approximately 1700 psi. The temperature was maintained at 40°C or increased to 50°C. The pressure was then increased in 1000 psi increments from approximately 2500 psi to approximately 6500 psi using a syringe pump. In the previous test, a temperature of 40°C and a pressure of 3500 psi were selected. The resulting solution was released in a burst for 0.5 seconds through a 5 μm nozzle. Figure 1A shows the CBD isolate before processing. The CBD isolate has a crystalline form and a large amount of aggregation between large particles. Figure 1B shows the CBD distillate after processing at a pressure of 3500 psi and a temperature of 40°C. The resulting distillate particles exhibited a more spherical amorphous morphology and had particle sizes ranging from 100 nm to 40 μm.

[0109] Example 3: Complexation with cyclodextrin To increase the solubility of cannabinoids in water, the cannabinoid extracts, distillates, and isolates produced as described in Example 1 were combined with α-cyclodextrin or β-cyclodextrin in a cannabinoid:cyclodextrin molar ratio ranging from 1:0.5 to 1:10 and added to a 10 ml reactor chamber. Supercritical CO2 was pumped into the reaction chamber at a pressure of 1,000 psi, the reactor chamber was heated to 40°C, and the pressure was increased to 3,500 psi. The resulting solution was released in a burst for 0.5 seconds through a 5 μm nozzle. Cyclodextrin was found to be insoluble under the process conditions.

[0110] To increase solubility in supercritical fluids, α-cyclodextrin and β-cyclodextrin were acetylated by substituting one or more hydroxyl groups with one or more acetyl groups, thereby increasing Lewis acid-Lewis base interactions in the supercritical fluid. 2.0 g of α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin was acetylated in 10 ml of anhydride acetic acid in a 100 ml round-bottom flask. 0.05 g of iodine was added to the mixture, and the flask was stirred in the dark for 2 hours. The reaction mixture was quenched with 50 ml of water, and 1% (w / w) aqueous sodium thiosulfate solution was added dropwise until the solution became clear. The reaction mixture was stirred for 1 hour, and the resulting solution was extracted four times with 40 ml of dichloromethane (DCM). The organic fractions were combined, washed twice with 50 ml of water, and dried over sodium sulfate before solvent removal. The final product was dried under vacuum to obtain α-cyclodextrin exadeacetate (AACD), β-cyclodextrin heneicosaacetate (ABCD), or γ-cyclodextrin octadecate (AGCD), respectively.

[0111] Next, acetylated cyclodextrin was added to a 10 ml reactor chamber in combination with cannabinoid extracts, distillates, and isolates in a cannabinoid:cyclodextrin molar ratio ranging from 1:0.5 to 1:10. Supercritical CO2 was pumped into the reaction chamber at a pressure of 1,000 psi, the reactor chamber was heated to 40°C, and the pressure was increased to 3,500 psi. The resulting solution was released in a burst for 0.5 seconds through a 5 μm nozzle.

[0112] The results showed that under experimental conditions, the solubility of AACD, ABCD, and AGCD in supercritical CO2 increased to 1.1% by weight and 1.3% by weight, respectively. Furthermore, cannabinoid complexation with acetylated cyclodextrin prevented the resuspension of cannabinoids and their impurities, such as terpenes and waxes, during processing.

[0113] Example 4: Preparation of Cannabinoid Ultrafine Nanoparticles Cannabinoid complexes containing acetylated cyclodextrin were prepared as described in Example 3 with cannabinoid:cyclodextrin molar ratios ranging from 1:0.5 to 1:10, and each was added to a 10 ml reactor chamber. The cannabinoid-cyclodextrin complexes were dissolved in a supercritical fluid at a pressure of 3500 psi and a temperature of 40°C. This solution was reduced in pressure through a 5 micron nozzle into a 19 liter expansion chamber with tubular exhaust to ensure maximum recovery of the fine particles. Figures 2A and 2B show the 32x and 200x magnification, respectively, of particles of CBD distillate complexed with α-cyclodextrin at a cannabinoid:cyclodextrin molar ratio of 1:2.5 w / w (250 mg of CBD complexed with 100 mg of α-cyclodextrin). The generated CBD nanoparticles exhibited a spherical morphology with particle sizes ranging from 100 nm to 40 μm. The addition of acetylated cyclodextrin produced a fine powder that did not resuspend after treatment, as shown in Figures 2A and 2B, suggesting integration of the CBD compound into the AACD ring.

[0114] Example 5: Bioavailability of Cannabinoid Ultrafine Nanoparticles The bioavailability of the cannabinoid ultrafine nanoparticles obtained as described in Example 4 was investigated by visually evaluating the solubility of the fine nanoparticles under simulated stomach conditions. 0.5 g of NaCl was added to a 0.155 M aqueous HCl solution to simulate stomach acid conditions. 10 mg of fine nanoparticles, 10 mg of crystalline isolate, and 10 mg of distillate were each placed in vials containing 10 ml of acidic solution and incubated at 37°C for 10 hours. At the end of the 10-hour period, only minimal solubility of the preparations was observed. An additional 10 ml of acidic solution was added, and the mixture was incubated at 37°C for 10 hours or more. At the end of the 20-hour period, the cannabinoid nanoparticles dissolved in the acidic solution. In contrast, the crystalline isolate and distillate showed complete insolubility (Figures 3-5).

[0115] Example 6: Relative bioavailability test of cannabinoid ultrafine nanoparticles Using a high-performance liquid chromatography (HPLC) separator equipped with a UV detector, the relative bioavailability of the cannabinoid ultrafine nanoparticles (test samples) obtained as described in Example 4 was compared to cannabinoid isolates in water (control samples) to determine the concentration of CBD in each sample. Control samples were prepared by filtering 1 ml of each sample through a 0.45 μm filter into 2 ml HPLC vials, and 1 ml of methanol (MeOH) was added to each sample vial. The HPLC mobile phase consisted of 65% acetonitrile and 35% water. A flow rate of 1 ml per minute resulted in CBD elution after approximately 4.5 minutes.

[0116] Percentage area was measured after 32 hours of elapsed time. This represents the amount of CBD in each sample compared to the background signal produced by MeOH in each sample. The percentage area of ​​the test samples was found to be 4.1163% of the total percentage area of ​​all control samples, compared to 0.7706% of the total percentage area of ​​all control samples.

[0117] These results indicate that the disclosed purified cannabinoid fine nanoparticles improve the solubility of CBD compared to a control cannabinoid isolate in water. The significant increase in solubility (up to 6 times in this case) suggests the potential for a dramatic improvement in the bioavailability of the disclosed formulation. A significant increase in bioavailability can dramatically improve therapeutic efficacy.

[0118] Example 7: Preparation of water-soluble cyclodextrin-encapsulated API nanoparticles To increase the solubility of the API in water, cannabinoid distillates, as described in Example 1, were combined with various cyclodextrins, and the resulting mixtures were placed in a high-pressure reactor. Liquefied CO2 was pumped into the reactor until the reactor pressure reached 5,000 psi. The mixtures were stirred in the reactor for 30 minutes to produce cyclodextrin-encapsulated cannabinoids. The mixtures were then sprayed into a cyclone to evaporate the CO2 and obtain a dry powder of cyclodextrin-encapsulated cannabinoids. The recovered CO2 was stored in a buffer tank for future use. Table 1 below shows the percentage of cannabinoid content in each sample. Table 1 also shows that the average percentage of cannabinoid content in cyclodextrin-encapsulated cannabinoid nanoparticles was 10 times higher than the average percentage of cannabinoid content in standard non-cyclodextrin-encapsulated cannabinoid nanoparticles. [Table 1]

[0119] Example 8: Dissolution profile of cyclodextrin-encapsulated API powder The solubility profiles were determined by dissolving the samples obtained from Example 7. Commercial THC oil (Reign Drops, THC 30 mg / ml) was used as a standard control. Each sample containing an equal volume of cannabinoid (40 mg) was dissolved in 200 ml of distilled water. The temperature was kept constant at 50°C.

[0120] At time intervals of 0.5, 1, 2, 3, 5, 10, 20, and 30 minutes, 2 ml of each sample solution was taken from the medium and immediately filtered through a 0.45 μm syringe filter. The filtered solutions were then analyzed by HPLC at a wavelength of 220 nm using 0.085% phosphoric acid in methanol and 0.085% phosphoric acid in water as mobile phases. The results, summarized in Table 2 and illustrated in Figure 9, show that over 90% of the cyclodextrin-encapsulated API dry powder dissolved in water. In contrast, only 26% of the standard control non-cyclodextrin-encapsulated cannabinoid dry powder dissolved in water. These results confirm that cyclodextrin-encapsulated APIs have superior bioavailability and efficacy compared to non-cyclodextrin-encapsulated APIs. [Table 2]

[0121] Example 9: In vivo absorption test of cyclodextrin-encapsulated cannabinoids Using baker's yeast (Saccharomyces cerevisiae), we measured transmembrane transport rates and evaluated the bioavailability of cyclodextrin-encapsulated cannabinoids compared to unencapsulated THC absorption over a 2-hour period.

[0122] Yeast was inoculated into a sugar solution and acclimatized at 35°C for 15 minutes. Half of the yeast culture was then treated with a solution containing unencapsulated THC as a control, and the other half was treated with an equal volume of THC in the form of cyclodextrin-encapsulated THC. The treatment was carried out at 35°C for 2 hours with gentle stirring to facilitate gas exchange. At the end of the treatment, the solution was removed by centrifugation, the yeast cells were washed and dissolved with physiological saline solution, and subjected to organic extraction. The organic cannabinoid solution was analyzed by HPLC. The results shown in Table 3 demonstrate that cyclodextrin microencapsulation improves THC transport and absorption across the yeast membrane by 200% compared to the transport of unencapsulated THC. Overall, these results demonstrate that cyclodextrin microencapsulation can improve cannabinoid absorption in eukaryotic systems such as humans, providing users with an enhanced recreational or medical experience. [Table 3]

[0123] It should be understood that the embodiments shown are merely examples of the methods disclosed and should not be considered to limit the scope of the invention. Rather, the scope of the invention is defined by the following claims.

Claims

1. A stable, non-degradable, edible, inhalable, soluble, or drinkable composition comprising a pharmaceutical-grade acetylated cyclodextrin-encapsulated active pharmaceutical ingredient (API) with 99.9% purity and 200% increased bioavailability compared to formulations of non-cyclodextrin-encapsulated active pharmaceutical ingredients, and a pharmaceutically acceptable carrier, excipient, emulsifier, and / or binder, The pharmaceutical-grade acetylated cyclodextrin-encapsulated active pharmaceutical ingredient is in the form of nanoparticles having an average particle size of 100 nm to 40 μm and a size distribution of 1% to 50% of the average particle size. The active pharmaceutical ingredient is a cannabinoid, The cannabinoid is one or more of cannabidiol (CBD) or (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), and A stable, non-degradable, edible, inhalable, soluble, or drinkable composition comprising acetylated cyclodextrin, acetylated α-cyclodextrin, acetylated β-cyclodextrin, acetylated γ-cyclodextrin, or a mixture thereof.

2. A stable, non-degradable, edible, inhalable, soluble, or drinkable composition according to claim 1, wherein the API and the one or more acetylated cyclodextrins are in a molar ratio of API:acetylated cyclodextrins in the range of 1:0.5 to 1:10, or the molar ratio of API:acetylated cyclodextrins is 1:0.5, 1:0.75, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, or 1:

10.

3. The stable, non-degradable, edible, inhalable, soluble, or drinkable composition according to claim 2, wherein the one or more cannabinoids comprises (-)-trans-Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), or a mixture thereof.

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